Hepatocellular carcinoma (HCC), the most common form of liver cancer, is the third leading cause of cancer-related deaths worldwide1. Clinical studies have demonstrated that fatty liver (hepatosteatosis) triggers an inflammatory response (steatohepatitis) due to fat- induced toxicities, eventually progressing to HCC10,11. While recent epidemiological studies revealed that obesity is an HCC risk factor3-5, it is not the only cause of liver fat accumulation. Therefore, a better mechanistic understanding of the development of these disease states is imperative. Autophagy, or "self-eating," is used to maintain homeostasis by recycling cellular building blocks through degradation of damaged cellular components15. The goal of this proposal is to use two independent mouse models of chemical-induced HCC12,24,30, that accurately represent human HCC9,28, to determine whether defective liver autophagy, which has been shown to suppress breakdown of liver lipids17, is to account for liver fat accumulation and HCC development in both obesity- and non-obesity-promoted HCC (Aim 1). Moreover, a novel molecular connection between STAT3, an activator of gene expression, and autophagy will be investigated, elucidating how autophagy is suppressed in HCC (Aim 2). Lastly, it will be examined whether stimulation of autophagy represses hepatosteatosis and HCC development (Aim 3). Combined, these studies will shed light on the cause of HCC and provide rationale for therapeutically activating autophagy in HCC patients. PUBLIC HEALTH RELEVANCE: The rising obesity epidemic in the United States6,7 and other developed countries threatens to increase the global rates of hepatocellular carcinoma (HCC) diagnosis and HCC- related deaths. As treatment options for HCC patients are limited at best, there is a dire need to further understand the molecular etiology of HCC to develop novel therapeutic options for patients. This proposal seeks to elucidate the role of defective autophagy in this disease and to uncover whether stimulating autophagy is an effective approach to disease regression.